Novel cycloalkyl derivatives as inhibitors of bone resorption and vitronectin receptor antagonists

ABSTRACT

There are described cycloalkyl derivatives of the formula (I) 
 
R 1 —Y-A-B-D-E-F-G   (I) 
 
in which R 1 , Y, A, B, D, E, F and G have the meaning indicated herein, their preparation and their use as medicaments. The compounds according to the invention can be used as vitronectin receptor antagonists and as inhibitors of bone resorption.

BACKGROUND OF THE INVENTION

1) Field of the Invention

The present invention relates to compounds of the formula I and theirphysiologically tolerable salts. The present invention also relates topharmaceutical preparations comprising such compounds, their preparationand use as medicaments, in particular as inhibitors of bone resorptionby osteoclasts, as inhibitors of tumor growth and tumor metastasis, asantiinflammatories, for the treatment or prophylaxis of cardiovasculardisorders such as arteriosclerosis or restenosis, for the treatment orprophylaxis of nephropathies and retinopathies, such as, for example,diabetic retinopathy, and as vitronectin receptor antaconists for thetreatment and prophylaxis of illnesses which are based on theinteraction between vitronectin receptors and their ligands in cell-cellor cell-matrix interaction processes. The invention furthermore relatesto the use of the compounds of the formula I and their physiologicallytolerable salts and pharmaceutical preparations comprising suchcompounds as medicaments for the alleviation or cure of illnesses whichare caused at least partially by an undesired extent of bone resorption,angiogenesis, or proliferation of cells of the vascular smoothmusculature.

2) Description of Related Art

Human bones undergo a continuous dynamic renovation process whichinvolves bone resorption and bone formation. These processes arecontrolled by types of cell specialized for this. Bone formation isbased on the deposition of bone matrix by osteoblasts, bone resorptionis based on the degradation of bone matrix by osteoclasts. The majorityof bone disorders are based on a disturbed equilibrium between boneformation and bone resorption. Osteoporosis is characterized by a lossof bone matrix. Activated osteoclasts are polynuclear cells having adiameter of up to 400 μm, which remove bone matrix. Activatedosteoclasts accumulate on the surface of the bone matrix and secreteproteolytic enzymes and acids into the so-called “sealing zone”, theregion between their cell membrane and the bone matrix. The acidenvironment and the proteases bring about the degradation of the bone.

Studies have shown that the accumulation of osteoclasts on the bone iscontrolled by integrin receptors on the cell surface of osteoclasts.

Integrins are a superfamily of receptors which include, inter alia, thefibrinogen receptor α_(IIb)βB₃ on the blood platelets and thevitronectin receptor α_(v)β₃. The vitronectin receptor α_(v)βB₃ is amembrane glycoprotein which is expressed on the cell surface of a numberof cells such as endothelial cells, cells of the vascular smoothmusculature, osteoclasts and tumor cells. The vitronectin receptorα_(v)β₃ which is expressed on the osteoclast membrane controls theprocess of accumulation on the bone and bone resorption and thuscontributes to osteoporosis.

α_(v)β₃ in this case binds to bone matrix proteins such as osteopontin,bone sialoprotein and thrombospontin, which contain the tripeptide motifArg-Gly-Asp (or RGD).

Horton and co-workers describe RGD peptides and an anti-vitronectinreceptor antibody (23C6), which inhibit tooth destruction by osteoclastsand the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991,195, 368). In J. Cell Biol. 1990. 111, 1713, Sato et al. describeechistatin, an RGD peptide from snake venom, as a potent inhibitor ofbone resorption in a tissue culture and as an inhibitor of osteoclastattachment to the bone. Fischer et al. (Endocrinology, 1993, 132, 1411)were able to show in the rat that echistatin also inhibits boneresorption in vivo.

The vitronectin receptor α_(v)β₃ on human cells of the vascular smoothmusculature of the aorta stimulates the migration of these cells intothe neointima, which finally leads to arteriosclerosis and restenosisafter angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).

Brooks et al. (Cell 1994, 79, 1157) show that antibodies against α_(v)β₃or α_(v)β₃ antagonists can bring about a shrinkage of tumors by inducingthe apoptosis of blood vessel cells during angiogenesis. Chersh et al.(Science 1995, 270, 1500) describe anti-α_(v)β₃ antibodies or α_(v)β₃antagonists which inhibit bFGF-induced angiogenesis processes in the rateye, which could be useful therapeutically in the treatment ofretinopathies.

The Patent Application WO 94/12181 describes substituted aromatic ornonaromatc ring systems and WO 94/08577 describes substitutedheterocycles as fibrinogen receptor antagonists and inhibitors ofplatelet aggregation. EP-A-518 586 and EP-A-528 587 disclose aminoalkyl-or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710discloses aryl derivatives as inhibitors of bone resorption byosteoclasts. WO 96/00574 describes benzodiazepines, and WO 96/00730describes fibrinogen receptor antagonist templates, in particularbenzodiazepines which are linked to a nitrogen-bearing 5-membered ring,as vitronectin receptor antagonists.

SUMMARY OF THE INVENTION

One object of the present invention is to provide compounds and theirpharmacologically tolerable salts capable of being used as inhibitors ofbone resorption by osteoclast, as inhibitors of tumor growth and tumormetastasis, as antiinflammatories, for the treatment or prophylaxis ofcardiovascular disorders such as arteriosclerosis or restenosis, for thetreatment or prophylaxis of nephropathies and retinopathies and asvitronectin receptor antagonists for the treatment and prophylaxis ofillnesses which are based on the interaction between vitronectinreceptors and their ligands in cell-cell or cell-matrix interactionprocesses. Another object of the invention is to provide compounds whichcan be used as carriers for active compounds in order to transfer theactive compounds specifically to the site of action.

Another object of the invention is to provide a pharmaceuticalpreparation which includes the compound of the present invention. Stillanother object of the invention is to provide methods for the productionof the compound of the present invention. Still another object of thepresent invention is to provide methods for the treatment of theconditions described above.

In accomplishing the foregoing objects, there has been providedaccording to one aspect of the present invention, cycloalkyl derivativesof the formula IR¹—Y-A-B-D-E-F-G   I.in which:

-   -   A is a direct bond, (C₁-C₈)-alkanediyl, —NR²—C(O)—NR²—,        —NR²—C(O)O—, —NR²—C(O)S—, —NR²—C(S)—NR²—, —NR²—C(S)—O—,        —NR²—C(S)—, —NR²(O)_(n)—NR²—, —NR²—S(O)_(n)—O—, —NR²—S(O)_(n)—,        (C₃-C₁₂)-cycoalkanediyl, —C≡C—, —NR²—C(O)—, —C(O)—NR²—,        —(C₁-C₁₄)-arylene-C(O)—NR²—, —O—, —S(O)_(n)—,        —(C₅-C₁₄)-arylene-, —CO—, —(C₅-C₁₄)-arylene-CO—, —NR²—,        —SO₂—NR²—, —CO₂—, —CR²═CR³—, —(C₅-C₁₄)-arylene-S(O)_(n)—, which        in each case can be mono- or disubstituted by        (C₁-C₈)-alkanediyl, such as, for example,        —(C₁-C₈)-alkanediyl-CO—NR²—(C₁-C₈)-alkanediyl,        —(C₁-C₈)-alkanediyl-CO—NR²— or —CO—NR²—(C₁-C₈)-alkanediyl;    -   B is a direct bond, (C₁-C₁₀)-alkanediyl, —CR²═CR³— or —C≡C—,        which in each case can be mono- or disubstituted by        (C₁-C₃)-alkanediyl, such as, for example, —CH₂—C≡C—CH₂— or        —CH₂—CR²═CR³—;    -   D is a direct bond, (C₁-C₈)-alkanediyl, —O—, —NR²—, —CO—NR²—,        —NR²—CO—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—,        —CO—, —CS—, —S(O)—, —S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)—,        —NR²—S(O)₂—, —S—, —CR²═CR³—, —C≡C—, or —CH(OH)—, which in each        case can be mono- or disubstituted by (C₁-C₈)-alkanediyl;    -   E is a 6-membered aromatic ring system, which optionally        contains up to 4 nitrogen atoms and is optionally substituted by        1-4 identical or different radicals from the group consisting of        R², R³, fluorine, Cl, Br, I, NO₂ and OH;    -   F is defined as D;

Y is a direct bond or —NR²—;

-   -   R¹ is R²—C(═NR²)—NR²—, R²R³N—C(═NR²)—, R²R³N—C(═NR²)—NR²—, or a        4-10-membered mono- or polycyclic aromatic or nonaromatic ring        system, which can optionally contain 14 heteroatoms from the        group consisting of N, O and S and can optionally be        monosubstituted or polysubstituted by substituents from the        group consisting of R¹¹, R¹², R¹³ and R¹⁴;    -   R², R³ independently of one another are H, (C₁-C₁₀)-alkyl which        is optionally mono- or polysubstituted by fluorine,        (C₃-C₁₂-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl,        (C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, H₂N,        (R⁸O)R⁸NR⁷, R⁸OR⁷, R⁸OC(O)R⁷, R⁸—(C₁-C₁₄)-arylene-R⁷, R⁸R⁸NR⁷,        HO—(C₁-C₈)-alkanediyl-NR⁸R⁷, R⁸R⁸NC(O)R⁷, R⁸C(O)NR⁸R⁷, R⁸C(O)R⁷,        R⁸R⁸N—C(═NR⁸)—, R⁸R⁸N—C(═NR⁸)—NR⁸— or        (C₁-C₁₈)-alkylcarbonyloxy-C₁-C₈)-alkanediyloxycarbonyl;    -   R⁴ is (C₁₀-C₁₈)-cycloalkyl,        (C₁₀-C₁₈)-cycloalkyl-(C₁-C₈)-alkanediyl, it being possible for        the cycloalkyl radicals to be mono- or polycyclic, saturated or        mono- or polyunsaturated and to be substituted as described in        the case of R⁶, or R⁶OR⁷, R⁶SR⁷, R⁶CO₂R⁷, R⁶OC(O)R⁷,        R⁶—(C₅-C₁₄)-arylene-R⁷, R⁶N(R²)R⁷, R⁶R⁶NR⁷, R⁶N(R²)C(O)OR⁹,        R⁶S(O)_(n)N(R²)R⁷, R⁶OC(O)N(R²)R⁷, R⁶C(O)N(R²)R⁷,        R⁶N(R²)C(O)N(R²)R⁷, R⁶N(R²)S(O)_(n)N(R²)R⁷, R⁶S(O)_(n)R⁷,        R⁶SC(O)N(R²)R⁷, R⁶C(O)R⁷, R⁶N(R²)C(O)R⁷, R⁶N(R²)S(O)_(n)R⁷;    -   R⁵ is H, fluorine, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-aryl,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, it being possible for the        alkyl radicals to be mono- or polysubstituted by fluorine;    -   R⁶ is (C₁₀-C₁₈)-cycloalkyl,        (C₁₀-C₁₈)-cycloalkyl-(C₁-C₈)-alkanediyl, it being possible for        the cycloalkyl radicals to be mono- or polycyclic, saturated or        mono- or polyunsaturated, and mono- or polysubstituted by        (C₁-C₁₀)-alkyl which is optionally mono- or poly-substituted by        fluorine, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-aryl,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, (C₁-C₈)-alkoxy,        (C₅-C₁₄)-aryl-(C₅-C₁₄)-alkanediyloxy, (C₅-C₁₄)-aryloxy,        (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy, NH₂, mono- or        di-(C₁-C₈-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylamino,        (C₅-C₁₄)-arylamino, ═O, ═S, NO₂, OH, fluorine, Cl, Br, or I;    -   R⁷ is a direct bond or (C₁-C₈)-alkanediyl;    -   R⁸ is H, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-aryl,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, it being possible for the        alkyl radicals to be mono- or polysubstituted by fluorine;    -   R⁹ is C(O)R¹⁰, C(S)R¹⁰, S(O)_(n)R¹⁰, P(O)(R¹⁰)_(n) or a four- to        eight-membered, saturated or unsaturated heterocycle which        contains 1, 2, 3 or 4 heteroatoms from the group N, O, S, such        as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl,        thiadiazolyl;    -   R¹⁰ is OH, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyloxy,        (C₅-C₁₄)-aryloxy,        (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylcarbonyloxy-(C₁-C₈)-alkanediyloxy,        NH₂, mono- or di-(C₁-C₈-alkyl)-amino,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylamino,        (C₁-C₈)-dialkylaminocarbonylmethylenoxy,        (C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethylenoxy or        (C₅-C₁₄)-arylamino or a radical of an L- or D-amino acid;    -   R¹¹, R¹², R¹³, R¹⁴ independently of one another are H,        (C₁-C₁₀)-alkyl, which is optionally mono- or polysubstituted by        fluorine, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-aryl,        (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, H₂N, (R⁸O)R⁸NR⁷, R⁸OR⁷,        R⁸OC(O)R⁷, R⁸R⁸NR⁷, R⁸—(C₅-C₁₄)-arylene-R⁷,        HO—(C₁-C₈)-alkanediyl-N(R²)R⁷, R⁸N(R²)C(O)R⁷, R⁸C(O)N(R²)R⁷,        R⁸C(O)R⁷, R²R³N—C(═NR²)—NR²—, R²R³N—C(═NR²)—, ═O, ═S;    -   n is 1 or 2;    -   q is 0 or 1;    -   in all their stereoisomeric forms and mixtures thereof in any        ratio;    -   and their physiologically tolerable salts.

According to another aspect of the present invention, there has beenprovided a pharmaceutical preparation comprising at least one compoundof the formula I and/or a physiologically tolerable salts thereof and atleast one pharmaceutically innocuous excipient and/or additive.

According to still another aspect of the present invention, there hasbeen provided a process for the preparation of a compound of the formulaI,R¹—Y-A-B-D-E-F-G   I.in which F is —C(O)NR²— and R¹, R², Y, A, B, D, E and G are defined asabove, which comprises carrying out a fragment condensation with acompound of the formula IIR¹—Y-A-B-D-E-M   II.where M is hydroxycarbonyl, (C₁-C₈)-alkoxycarbonyl or activatedcarboxylic acid derivatives and R¹, Y, A, B, D and E have theabovementioned meaning, and HNR²-G, in which R² and G are as definedabove.

According to yet another aspect of the present invention, there has beenprovided a process for the preparation of a compound of the formula I,R¹—Y-A-B-D-E-F-G   I,in which R¹—Y-A- is

or a cyclic acylguanidine of the type

and R², R³, B, D, E, F and G are defined as above, which comprisesreacting a compound of the formula IIIQ(O)C—B-D-E-F-G   IIIin which Q is an easily nucleophilically substitutable leaving group andB, D, E, F and G are as defined above, with the appropriate guanidine(derivative) of the type

or the cyclic guanidine (derivative)

in which R² and R³ are as defined above.

According to another aspect of the present invention, there has beenprovided a method for inhibiting bone resorption by osteoclasts,inhibiting tumor growth and tumor metastasis, reducing inflammation,treating or preventing cardiovascular disorders, for treating orpreventing nephropathies and retinopathies or for the treatment andprevention of diseases which are based on the interaction betweenvitronectin receptors and their ligands in cell-cell or cell-matrixinteraction processes, comprising administering a therapeuticallyeffective amount of the compound of the formula I and/or aphysiologically tolerable salt thereof to a human or animal in needthereof.

Further objects, features and advantages of the present invention willbecome apparent from the detailed description of preferred embodimentswhich follows.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The alkyl radicals occurring in the substituents of the compound offormula I can be straight-chain or branched, saturated or mono- orpolyunsaturated. The same applies to radicals derived therefrom, suchas, for example, alkoxy.

Cycloalkyl radicals in R², R³, R⁵, R⁸ and R¹¹-R¹⁴ can be mono-, bi- ortricyclic.

Monocyclic cycloalkyl radicals in R², R³, R⁵, R⁸ and R¹-R¹⁴ can include,in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, which, however, can also be substituted by,for example, (C₁-C₄)-alkyl. Examples of substituted cycloalkyl radicalswhich may be mentioned are 4-methylcyclohexyl and2,3-dimethylcyclopentyl. Examples of parent substances of monocyclic(C₁₀-C₁₈)-cycloalkyl radicals in R⁴ and R⁶ are, for example, cyclodecaneor cyclododecane.

Bicyclic and tricyclic cycloalkyl radicals in R², R³, R⁵, R⁸ and R¹¹-R¹⁴can be unsubstituted or substituted in any desired suitable positions byone or more oxo groups and/or one or more identical or different(C₁-C₄)-alkyl groups, e.g. methyl or isopropyl groups, preferably methylgroups. Bicyclic and tricyclic (C₁₀-C₁₈)-cycloalkyl radicals in R⁴ andR⁶ can be substituted as described there. The free bond of the bi- orthe tricyclic radical can be located in any desired position in themolecule; the radical can thus be bonded via a bridgehead atom or anatom in a bridge. The free bond can also be located in any desiredstereochemical position, for example in an exo- or an endo-position.

An example of a bicyclic ring system is decalin (decahydronaphthalene),an example of a system substituted with an oxo group is 2-decalone.

Examples of parent substances of tricyclic systems are twistane(=tri-cyclo(4.4.0.0-^(3,8)]decane), adamantane(=tricyclo(3.3.1.1^(3,7)]decane), noradamantane(=tricyclo(3.3.1.0^(3,7)]nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo(5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo(5.5.1.0^(3,11)]tridecane.

Examples of parent substances of tricyclic (C₁₀-C₁₈)-cycloalkyl radicalsin R⁴ and R⁶ are twistane (=tricyclo(4.4.0.0^(3,8)]decane), adamantane(=tricyclo(3.3.1.1^(3,7)]decane), noradamantane(=tricyclo(3.3.1.0^(3,7)]-nonane), tricyclo(5.3.2.0^(4,9)]dodecane,tricyclo(5.4.0.0^(2,9)]undecane or tricyclo(5.5.1.0^(3,11)]tridecane.

Examples of 6-membered aromatic ring systems are phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, tetrazinyl.

Aryl is for example, phenyl, naphthyl, biphenylyl, anthryl or fluorenyl,1-naphthyl, 2-naphthyl and in particular phenyl being preferred. Arylradicals, in particular phenyl radicals, can be mono- orpolysubstituted, preferably mono-, di- or trisubstituted, by identicalor different radicals from the group consisting of (C₁-C₈)-alkyl, inparticular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy,halogen, such as fluorine, chlorine and bromine, nitro, amino,trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl,aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl,benzyloxy, tetrazolyl, (R¹⁷O)₂P(O)— and (R¹⁷O)₂P(O)—O—, where R¹⁷ is H,(C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl or (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl.

In monosubstituted phenyl radicals, the substituent can be located inthe 2-, the 3- or the 4-position, with the 3- and the 4-position beingpreferred. If phenyl is disubstituted, the substituents can be in the1,2-, 1,3- or 1,4-position relative to one another. Preferably, indisubstituted phenyl radicals the two substituents are arranged in the3- and the 4-position, relative to the linkage site.

Aryl groups can furthermore be mono- or polycyclic aromatic ring systemsin which 1 to 5 carbon atoms can be replaced by 1 to 5 heteroatoms, suchas, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl, or a benzo-fused,cyclopenta-, cyclohexa- or cyclohepta-fused derivative of theseradicals. These heterocycles can be substituted by the same substituentsas the abovementioned carbocyclic aryl systems.

In the series of these aryl groups, mono- or bicyclic aromatic ringsystems having 1-3 heteroatoms from the group consisting of N, O, S, arepreferred, which can be substituted by 1-3 substituents from the groupconsisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, fluorine, Cl, NO₂, NH₂,trifluoromethyl, OH, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyloxyor benzyl.

Particularly preferred in this case are mono- or bicyclic aromatic5-10-membered ring systems having 1-3 heteroatoms from the series N, O,S, which can be substituted by 1-2 substituents from the groupconsisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenyl, phenoxy, benzyl orbenzyloxy.

L- or D-amino acids can be natural or unnatural amino acids. α-Aminoacids are preferred. Examples which may be mentioned are (cf.Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val,tert-butyiglycine (Tbg), neopentylglycine (Npg), cyclohexylglycsne(Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia),2,2-diphenylamincacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid,2-(p-chlorophenyi)aminoacetic acid.

The amino acids can furthermore include: pyrrolidine-2-carboxylic acid;piperidine-2-carboxylic acid;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo(2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro(4.4]nonane-3-carboxylic acid:2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo(2.2.2]octane)-2.3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1^(6,9)]decane-3-carboxylic acid;decahydrocyclohepta-[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid,all of which can be optionally substituted (see following formulae):

The heterocycles on which the abovementioned radicals are based aredisclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No.4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020: EP-A 52,870:EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A105,102: EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.

The amino acids can furthermore also be present as esters or amides,such as, for example, the methyl ester, ethyl ester, isopropyl ester,isobutyl ester, tert-butyl ester, benzyl ester, ethyl amide,semicarbazide or ω-amino-(C₂-C₈)-alkyl amide.

Functional groups of the amino acids can be present in protected form.Suitable protective groups such as, for example, urethane protectivegroups, carboxyl protective groups and side chain protective groups aredescribed in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 andin Büllesbach, Kontakte (Merck) 1980. No. 1, pages 23 to 35. Thefollowing may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z,Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂), Z(Hal_(n)), Bobz, Iboc, Adpoc,Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerable salts of the compounds of the formula I are,in particular, pharmaceutically utilizable or nontoxic salts. Such saltsare formed, for example, from compounds of the formula I which containacidic groups, e.g. carboxyl, with alkali metals or alkaline earthmetals, such as, for example, Na, K, Mg and Ca, and with physiologicallytolerable organic amines, such as, for example, triethylamine,ethanolamine or tris(2-hydroxyethyl) amine. Compounds of the formula Iwhich contain basic groups, e.g. an amino group, an amidino group or aguanidino group, form salts with inorganic acids, such as, for example,hydrochloric acid, sulfuric acid or phosphoric acid, and with organiccarboxylic or sulfonic acids, such as, for example, acetic acid, citricacid, benzoic acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid.

The compounds of the formula I according to the invention can containoptically active carbon atoms which independently of one another canhave R or S configuration and can thus be present in the form of pureenantiomers or pure diastereomers or in the form of enantiomer mixturesor diastereomer mixtures. The present invention relates both to pureenantiomers and enantiomer mixtures and to diastereomers anddiastereomer mixtures. The invention covers mixtures of twostereoisomers and of more than two sterecisomers of the formula I andall ratios of stereoisomers in the mixtures.

If A, D and F independently of one another are —CR²═CR³—, the compoundsof the formula I according to the invention can be present as E/Z isomermixtures. The present invention relates to both pure E and Z isomers andto mixtures of E/Z isomers in all ratios. Diastereomers, including E/Zisomers, can be separated into the individual isomers by chromatography.Racemates can either be separated into the two enantiomers bychromatography on chiral phases or by resolution.

The compounds of the formula I according to the invention can moreovercontain mobile hydrogen atoms. i.e. be present in various tautomericforms. The present invention also relates to these tautomers.

Preferred compounds of the formula I are those in which:

-   -   A is a direct bond, (C₁-C₆)-alkanediyl, —NR²—C(O)—NR²—,        —NR²—C(O)O—, —NR²—C(O)S—, —NR²—C(S)—NR²—, —NR²—C(S)—O—,        —NR²—C(S)—S—, —NR²—S(O)_(n)—NR²—, —NR²—S(O)_(n)—O—,        —NR²—S(O)_(n)—, (C₃-C₈)-cycloalkanediyl, —C≡C—, —NR²—C(O)—,        —C(O)—NR²—, —(C₅-C₁₂-arylene-C(O)—NR²—, —O—, —S(O)_(n)—,        —(C₅-C₁₂)-arylene-, —CO—, —(C₅-C₁₂-arylene-CO—, —NR²—,        —SO₂—NR²—, —CO₂—, —CR₂═CR³—, —(C₅-C₁₂)-arylene-S(O)_(n)—, which        in each case can be mono- or disubstituted by        (C₁-C₈)-alkanediyl;    -   B is a direct bond, (C₁-C₈)-alkanediyl, —CR²═CR³— or —C≡C—,        which in each case can be mono- or disubstituted by        (C₁-C₈)-alkanediyl;    -   D is a direct bond, (C₁-C₈)-alkanediyl or —O—, —NR²—, —CO—NR²—,        —NR²—CO—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—,        —CO—, —CS—, —S(O)—, —S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)—,        —NR²—S(O)₂—, —S—, —CR²═CR³—, —C≡C—, which in each case can be        mono- or disubstituted by (C₁-C₈)-alkanediyl;    -   E is a 6-membered aromatic ring system, which optionally        contains 1 or 2 nitrogen atoms and is optionally substituted by        1-3 identical or different radicals from the group consisting of        R², R³, fluorine, Cl and OH:    -   F is defined as D;    -   Y is a direct bond or —NR²—;    -   R¹ is R²—C(═NR²)—NR²—, R²R³N—C(═NR²)—, R²R³N—C(═NR²)—NR²—, or a        4-10- membered mono- or polycyclic aromatic or nonaromatic ring        system which can optionally contain 1-4 heteroatoms from the        group consisting of N, O and S and can optionally be        monosubstituted or polysubstituted by substituents from the        group consisting of R¹¹, R¹², R¹³ and R¹⁴;    -   R², R³ independently of one another are H, (C₁-C₈)-alkyl which        is optionally mono- or polysubstituted by fluorine, (C₃-C₅)        cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkanediyl,        (C₅-C₁₂)-aryl, (C₅-C₁₂)-aryl-(C₁-C₈)-alkanediyl, H₂N,        (R⁸O)R⁸NR⁷, R⁸OR⁷, R⁸OC(O)R⁷, R⁸—(C₅-C₁₂)-arylene-R⁷, R⁸R⁸NR⁷,        HO—(C₁-C₈)-alkanediyl-NR⁸R⁷, R⁸R⁸NC(O)R⁷, R⁸C(O)NR⁸R⁷, R⁸C(O)R⁷,        R⁸R⁸N—C(═NR⁸)—, R⁸R⁸N—C(═NR⁸)—NR⁸— or        (C₁-C₁₀)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxycarbonyl;    -   R⁴ is (C₁₀-C₁₆)-cycloalkyl,        (C₁₀-C₁₆)-cycloalkyl-(C₁-C₈)-alkanediyl, it being possible for        the cycloalkyl radicals to be mono- or polycyclic, saturated or        mono- or polyunsaturated and to be substituted as described in        the case of R⁶, or R⁶OR⁷, R⁶SR⁷, R⁶CO₂R⁷, R⁶OC(O)R⁷,        R⁶—(C₅-C₁₂-arylene-R⁷, R⁶N(R²)R⁷, R⁶R⁸NR⁷, R⁶N(R²)C(O)OR⁷,        R⁶S(O)_(n)N(R²)R⁷, R⁶OC(O)N(R²)R⁷, R⁶C(O)N(R²)R⁷,        R⁶N(R²)C(O)N(R²)R⁷, R⁶N(R²)S(O)_(n)N(R²)R⁷, R⁶S(O)_(n)R⁷,        R⁶SC(O)N(R²)R⁷, R⁶C(O)R⁷, R⁶N(R²)C(O)R⁷, R⁶N(R²)S(O)_(n)R⁷;    -   R⁵ is H, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl,        (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkanediyl, (C₅-C₁₀)-aryl,        (C₅-C₁₀)-aryl-(C₁-C₆)-alkanediyl, it being possible for the        alkyl radicals to be mono- or polysubstituted by fluorine;    -   R⁶ is (C₁₀-C₁₆)-cycloalkyl,        (C₁₀-C₁₆)-cycloalkyl-(C₁-C₆)-alkanediyl, it being possible for        the cycloalkyl radicals to be bi- or tricyclic, saturated or        mono- or polyunsaturated, and mono- or polysubstituted by        (C₅-C₆)-alkyl, which is optionally mono- or polysubstituted by        fluorine, (C₅-C₆)-cycloalkyl,        (C₅-C₆)-cycloalkyl-(C₁-C₆)-alkanediyl, (C₅-C₁₀)-aryl,        (C₅-C₁₀)-aryl-(C₁-C₅)-alkanediyl, (C₁-C₅)-alkoxy,        (C₅-C₁₀)-aryloxy, (C₅-C₁₀)-aryl-(C₁-C₅)-alkanediyloxy, NH₂,        mono- or di-(C₁-C₅-alkyl)-amino, ═O, OH, fluorine or Cl;    -   R⁷ is a direct bond or (C₁-C₆)-alkanediyl;    -   R⁸ is H, (C₁-C₆)-alkyl, (C₃-C₅)-cycloalkyl,        (C₃-C₅)-cycloalkyl-(C₁-C₅)-alkanediyl, (C₅-C₁₂)-aryl,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkanediyl, it being possible for the        alkyl radicals to be mono- or polysubstituted by fluorine;    -   R⁹ is C(O)R¹⁰, C(S)R¹⁰, S(O)_(n)R¹⁰, P(O)(R¹⁰)_(n) or a four to        eight-membered, saturated or unsaturated heterocycle which        contains 1, 2, 3 or 4 heteroatoms from the group consisting of        N, O, S;    -   R¹⁰ is OH, (C₁-C₅)-alkoxy, (C₅-C₁₂-aryl-(C₁-C₆)-alkanediyloxy,        (C₅-C₁₂)-aryloxy,        (C₁-C₅)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy,        (C₅-C₁₂)-aryl-(C₁-C₅)-alkanediylcarbonyloxy-(C₁-C₅)-alkanediyloxy,        NH₂, mono- or di-(C₁-C₆-alkyl)-amino,        (C₅-C₁₂)-aryl-(C₁-C₅)-alkanediylamino,        (C₁-C₆)-dialkylaminocarbonyl-methylenoxy;    -   R¹¹, R¹², R¹³, R¹⁴ independently of one another are H,        (C₁-C₈)-alkyl, which is optionally mono- or polysubstituted by        fluorine, (C₃-C₅)-cycloalkyl,        (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkanediyl, (C₅-C₁₂)-aryl,        (C₅-C₁₂)-aryl-(C₁-C₅)-alkanediyl, H₂N, (R⁸O)R⁸NR⁷, R⁸OR⁷,        R⁸OC(O)R⁷, R⁸—(C₅-C₁₂)-arylene-R⁷, R⁸R⁸NR⁷,        HO—(C₁-C₈)-alkyl-N(R²)R⁷, R⁸N(R²)C(O)R⁷, R⁸C(O)N(R²)R⁷,        R⁸C(O)R⁷, R²R³N—C(═NR²)—, R²R³N—C(═NR³)—NR²—, ═O, 50 S;    -   n is 1 or 2;

q is 0 or 1;

-   -   in all their stereoisomeric forms and mixtures thereof in any        ratio;    -   and their physiologically tolerable salts.

Particularly preferred compounds of the formula I are those in which:

-   -   A is a direct bond, (C₁-C₆)-alkanediyl, —NR²—C(O)—NR²—,        —NR²—C(O)O—, —NR²—S(O)_(n)—NR²—, —NR²—S(O)_(n)—,        (C₃-C₆)-cycoalkanediyl, —C≡C—, —NR²C(O)—, —C(O)—NR²—, —O—, —CO—,        —NR²—, —CO—, —CR²═CR³—, which in each case can be mono- or        disubstituted by (C₁-C₅)-alkanediyl;    -   B is a direct bond, (C₁-C₆)-alkanediyl, —CR²═CR³—, which can be        mono- or disubstituted by (C₁-C₆)-alkanediyl;    -   D is a direct bond, (C₁-C₆)-alkanediyl or —O—, —NR²—, —NR²—CO—,        —(O)—NR²—S(O)₂—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)—, —S(O)₂—NR²—,        —NR²—S(O)—, —NR²—S(O)₂, which in each case can be mono- or        disubstituted by (C₁-C₆)-alkanediyl;    -   E is phenylene or pyridinediyl which is optionally substituted        by 1-3 identical or different radicals from the group consisting        of R² and R³;    -   F is a direct bond, (C₁-C₆)-alkanediyl, or —O—, —CO—NR²,        —NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —CO—, —S(O)₂—,        —S(O)₂—NR²—, —NR²—S(O)₂—, —CR²═CR³—, —C≡C—, which in each case        can be mono- or disubstituted by (C₁-C₆)-alkanediyl;    -   Y is a direct bond or —NH—;    -   R¹ is R²—C(═NR²)—NR²—, R²R³N—C(═NR²)—.    -   R², R³ independently of one another are H, (C₁-C₆)-alkyl which        is optionally mono- or polysubstituted, preferably 16 times, by        fluorine, (C₃-C₆)-cycloalkyl,        (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkanediyl, (C₅-C₁₀)-aryl,        (C₅-C₁₀)-aryl-(C₁-C₄)-alkanediyl, H₂N, R⁸OR⁷,        R⁸—(C₅-C₁₀)-arylene-R⁷, R⁸NHR⁷, R⁸R⁸NR⁷, R⁸NHC(O)R⁷,        H₂—NC(═NH)—, H₂N—C(═NH)—NH—;    -   R⁴ is (C₁₀-C₁₄)-cycloalkyl,        (C₁₀-C₁₄)-cycloalkyl-C₁-C₆)-alkanediyl, it being possible for        the cycloalkyl radicals to be bi- or tricyclic, and to be        substituted 1-3 times by (C₁-C₅)-alkyl, trifluoromethyl,        pentafluoroethyl, phenyl, benzyl, (C₁-C₅)-alkoxy, phenoxy,        benzyloxy, NH₂, ═O or mono- or di-(C₁-C₆-alkyl)-amino; or R⁶OR⁷,        R⁶CO₂R⁷, R⁶OC(O)R⁷, R⁶NHR⁷, R⁶R⁸NR⁷, R⁶NHC(O)OR⁷,        R⁶S(O)_(n)NHR⁷, R⁶OC(O)NHR⁷, R⁶C(O)NHR⁷, R⁶C(O)R⁷, R⁶NHC(O)NHR⁷,        R⁶NHC(O)R⁷;    -   R⁵ is H, (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl,        (C₅-C₆)-cycloalkyl-(C₁-C₆)-alkanediyl, trifluoromethyl,        pentafluoroethyl, phenyl, benzyl;    -   R⁶ is (C₁₀-C₁₄)-cycloalkyl,        (C₁₀-C₁₄)-cycloalkyl-(C₁-C₅)-alkanediyl, it being possible for        the cycloalkyl radicals to be bi- or tricyclic, and to be        substituted 1-3 times by (C₁-C₅)-alkyl, trifluoromethyl,        pentafluoroethyl, phenyl, benzyl, (C₁-C₆)-alkoxy, phenoxy,        benzyloxy, NH₂, ═O or mono- or di-(C₁-C₆-alkyl)-amino;    -   R⁷ is a direct bond or (C₁-C₅)-alkanediyl;    -   R⁸ is H, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,        (C₃-C₆)-Cycloalkyl-(C₁-C₄)-alkanediyl, (C₅-C₁₀)-aryl,        (C₅-C₁₀)-aryl-(C₁-C₄)-alkanediyl, it being possible for the        alkyl radicals to be substituted by 1-6 fluorine atoms;    -   R⁹ is C(O)R¹⁰;    -   R¹⁰ is OH, (C₁-C₅)-alkoxy, (C₅-C₁₀)-aryl-(C₁-C₆)-alkanediyloxy,        (C₅-C₁₀)-aryloxy,        (C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy,        (C₅-C₁₀)-aryl-(C₁-C₄)-alkanediylcarbonyloxy-(C₁-C₄)-alkanediyloxy,        NH₂, mono- or di-(C₁-C₆-alkyl)-amino;    -   R¹¹ is H, (C₁-C₆)-alkyl which is optionally mono- or        polysubstituted by fluorine, (C₃-C₆)-cycloalkyl,        (C₃-C₅)-cycloalkyl-(C₁-C₄)-alkanediyl, (C₅-C₁₀)-aryl,        (C₅-C₁₀)-aryl-(C₁-C₄)-alkanediyl, H₂N, R⁸OR⁷, R⁸OC(O)R⁷,        R⁸—(C₅-C₁₀)-arylene-R⁷, R⁸R⁸NR⁷, R⁸NHC(O)R⁷, R⁸C(O)NHR⁷,        H₂N—C(═NH)—, H₂N—C(═NH)—NH—, ═O;    -   n is 1 or 2;    -   q is 0 or 1;    -   in all their stereoisomeric forms and mixtures thereof in any        ratio;    -   and their physiologically tolerable salts.

Very particularly preferred compounds of the formula I are those inwhich:

-   -   A is a direct bond, (C₁-C₄)-alkanediyl, —NR²—C(O)—NR²—,        —NR²—C(O)O—, —NR²—S(O)_(n)—, —NR²—S(O)_(n)—NR²—, —NR²—CO— or        —NR²—, which in each case can be mono- or disubstituted by        (C₁-C₄)-alkanediyl;    -   B is a direct bond or (C₁-C₄)-alkanediyl;    -   D is a direct bond, (C₁-C₄)-alkanediyl or —O—, —NR²—, —NR²—CO—,        —C(O—NR²—, —NR²—C(O)—NR²—, which in each case can be mono- or        disubstituted by (C₁-C₄)-alkanediyl;    -   E is phenylene or pyridinediyl which is optionally substituted        by 1 or 2 radicals from the group consisting of R², R³;    -   F is a direct bond, (C₁-C₆)-alkanediyl, or —O—, —CO—NR²—,        —NR²—CO—, —NR²—C(O)—NR²—, —S(O)₂—NR²—, —NR²—S(O)₂—, —CR²═CR³—,        —C≡C—, which in each case can be mono- or disubstituted by        (C₁-C₄)-alkanediyl;    -   Y is a direct bond or —NH—;    -   R¹ is R²R³N—C(═NR²)—,    -   R², R³ independently of one another are H, (C₁-C₆)-alkyl,        trifluoromethyl, pentafluoroethyl, (C₅-C₆)-cycloalkyl,        (C₅-C₈)-cycloalkyl-(C₁-C₂)-alkanediyl, phenyl, benzyl, H₂N,        R⁸R⁷, R⁸R⁸NR⁷, R⁸NHC(O)R⁷, H₂N—C(═NH)—, H₂N—C(═NH)—NH—;    -   R⁴ is (C₁₀-C₁₂)-cycloalkyl,        (C₁₀-C₁₂)-cycloalkyl-(C₁-C₆)-alkanediyl, or R⁶OR⁷, R⁶R⁸NR⁷,        R⁶NHC(O)OR⁷, R⁶S(O)_(n)NHR⁷, R⁶C(O)NHR⁷, R⁶C(O)NHR⁷, the        cycloalkyl radicals preferably being 1-adamantyl or 2-adamantyl        and the cycloalkylalkanediyl radicals preferably being        adamantyl-1-(C₁-C₃)-alkanediyl or adamantyl-2-(C₁-C₃)-alkanediyl        and it being possible for them to be substituted 1 or 2 times by        (C₁-C₄)-alkyl, trifluoromethyl, phenyl, benzyl, (C₁-C₄)-alkoxy,        phenoxy, benzyloxy, ═O or mono- or di-(C₁-C₄-alkyl)-amino,        adamantyl radicals substituted 1 or 2 times as described above        or (C₁₁-C₁₂)-cycloalkyl radicals which are unsubstituted or        substituted 1 or 2 times as described above being particularly        preferred;    -   R⁵ is H, (C₁-C₄)-alkyl, trifluoromethyl;    -   R⁶ is (C₁₀-C₁₂)-cycloalkyl,        (C₁₀-C₁₂)-cycloalkyl-(C₁-C₆)-alkanediyl, the cycloalkyl radicals        preferably being 1 -adamantyl or 2-adamantyl and the        cycloalkylalkanediyl radicals preferably being        adamantyl-1-(C₁-C₃)-alkanediyl or adamantyl-2-(C₁-C₃)-alkanediyl        and it being possible for them to be substituted 1 or 2 times by        (C₁-C₄)-alkyl, trifluoromethyl, phenyl, benzyl, (C₁-C₄)-alkoxy,        phenoxy, benzyloxy, ═O or mono- or di-(C₁-C₄-alkyl)-amino,        adamantyl radicals substituted 1 or 2 times as described above        or (C₁₁-C₁₂)-cycloalkyl radicals which are unsubstituted or        substituted 1 or 2 times as described above being particularly        preferred;    -   R⁷ is a direct bond or (C₁-C₆)-alkanediyl;    -   R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl,        (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkanediyl, (C₅-C₆)-aryl,        (C₅-C₆)-aryl-C₁-C₂)-alkanediyl;    -   R⁹ is C(O)R¹⁰;    -   R¹⁰ is OH, (C₁-C₆)-alkoxy, phenoxy, benzyloxy,        (C₁-C₄)-alkylcarbonyloxy-C₁-C₄)-alkanediyloxy, NH₂, mono- or        di-(C₁-C₆-alkyl)-amino;    -   n is 1 or 2;    -   q is 0 or 1;    -   in all their stereoisomeric forms and mixtures thereof in any        ratio;    -   and their physiologically tolerable salts.

Especially preferred compounds of the formula I are those in which:

-   -   A is —NH—C(O)—;    -   B is (C₁-C₄)-alkanediyl;    -   D is —O—, —NR²—C(O)—, —(O)—NR²— or a direct bond;    -   E is phenylene or pyridinediyl;    -   F is —CH₂— or —C(O)NHCH₂—;    -   Y is a direct bond;    -   R¹ is H₂N—C(═NH)—,    -   R² is H or (C₁-C₄)-alkyl;    -   R⁴ is R⁶OC(O)NH—;    -   R⁵ is H:    -   R⁶ is adamantyl-1-(C₁-C₃)-alkylene,        adamantyl-2-(C₁-C₃)-alkylene, 1-adamantyl, 2-adamantyl,        adamantyl preferably being substituted 1 or 2 times by        (C₁-C₄)-alkyl, trifuoromethyl, phenyl, benzyl, (C₁-C₄)-alkoxy,        phenoxy or benzyloxy, or (C₁₁-C₁₂)-cycloalkyl which can be        substituted 1 or 2 times as above;    -   R⁹ is C(O)R¹⁰;    -   R¹⁰ is OH, (C₁-C₆)-alkoxy, phenoxy, benzyloxy or        (C₁-C₄)-alkoxycarbonyloxy-(C₁-C₄)-alkanediyloxy;    -   in all their stereoisomeric forms and mixtures thereof in any        ratio;    -   and their physiologically tolerable salts.

Compounds of the formula I can generally be prepared, for example in thecourse of a convergent synthesis, by linkage of two or more fragmentswhich can be derived retrosynthetically from the formula I. In thepreparation of the compounds of the formula I, it may generally benecessary in the course of the synthesis temporarily to block functionalgroups which could lead to undesired reactions or side reactions in therespective synthesis step by means of a protective group strategy suitedto the synthesis problem and known to the person skilled in the artusing the present specification as a guide. The method of fragmentcoupling is not restricted to the following examples, but is generallyapplicable for syntheses of the compounds of the formula I.

For example, compounds of the formula I of the typeR¹—Y-A-B-D-E-C(O)NR²-G,where F in the formula I is —C(O)NR²— can be prepared by condensation ofa compound of the formula IIR¹—Y-A-B-D-E-M   II,where M is hydroxycarbonyl, (C₁-C₅)-alkoxycarbonyl, activated carboxylicacid derivatives such as acid chlorides, active esters or mixedanhydrides, with HNR²-G. For the condensation of two fragments withformation of an amide bond, the coupling methods of peptide chemistryknown per se (see, for example, Houben-Weyl, Methoden der OrganischenChemie [Methods of Organic Chemistry], Volume 15/1 and 15/2. GeorgThieme Verlag, Stuttgart, 1974) are advantageously used. For thispurpose, as a rule it is necessary to protect nonreacting amino groupspresent during the condensation by reversible protective groups. Thesame applies to carboxyl groups not participating in the reaction, whichare preferably employed as (C₁-C₆)-alkyl, benzyl or tert-butyl esters.Amino group protection is unnecessary if the amino groups to begenerated are still present as nitro or cyano groups and are formed byhydrogenation only after coupling. After coupling, the protective groupspresent are removed in a suitable manner. For example, NO₂ groups(guanidino protection), benzyloxycarbonyl groups and benzyl esters canbe removed by hydrogenation. The protective groups of the tert-butyltype are cleaved under acidic conditions, while the9-fluorenylmethyloxycarbonyl radical is removed by secondary amines.

Compounds of the formula I in which R¹ has the meaning indicated, Y is—NR²—and A is —C(O)— can be prepared, for example, by the generallyknown coupling methods of peptide chemistry by coupling R¹—NR²H withHO₂C—B-D-E-F-G.

Compounds of the formula I where R⁹═SO₂R¹⁰ are prepared, for example, byoxidizing compounds of the formula I where R⁹═SH by processes known fromthe literature (cf. Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry], Vol. E12/2. Georg Thieme Verlag,Stuttgart 1985, p. 1058 et seq.) to compounds of the formula I whereR⁹═SO₃H, from which the compounds of the formula I whereR⁹═SO₂R¹⁰(R¹⁰≠OH) are then prepared directly or via correspondingsulfonic acid halides by esterification or linkage of an amide bond.Oxidation-sensitive groups in the molecule, such as, for example, amino,amidino or guanidino groups are protected, if necessary, by suitableprotective groups before carrying out the oxidation.

Compounds of the formula I where R⁹═S(O)R¹⁰ are prepared, for example,by converting compounds of the formula I where R⁹═SH into thecorresponding sulfide (R⁹═S^(⊖)) and then oxidizing withmeta-chloroperbenzoic acid to the sulfinic acids (R⁹═SO₂H) (cf.Houben-Weyl, Methoden der Organischen Chemie (Methods of OrganicChemistry], Vol. E11/1. Georg Thieme Verlag, Stuttgart 1985, p. 618 etseq.), from which the corresponding sulfinic acid esters or amidesR⁹═S(O)R¹⁰ (R¹⁰≠OH) can be prepared by methods known from theliterature. Generally, other methods known from the literature can alsobe used for the preparation of compounds of the formula I whereR⁹═S(O)_(n)R¹⁰ (n=1, 2) (cf. Houben-Weyl, Methoden der OrganischenChemie [Methods of Organic Chemistry], Vol. E11/1, Georg Thieme Verlag,Stuttgart 1985, p. 618 et seq. or Vol. E11/2, Stuttgart 1985, p. 1055 etseq.).

Compounds of the formula I where R⁹═P(O)(R¹⁰)_(n) (n=1, 2) aresynthesized from suitable precursors by processes known from theliterature (cf. Houben-Weyl, Methoden der Organischen Chemie (Methods ofOrganic Chemistry], Vol. E1 and E2, Georg Thieme Verlag, Stuttgart1982), the synthesis method selected being suited to the targetmolecule.

Compounds of the formula I where R⁹═C(S)R¹⁰ can be prepared by processesknown from the literature (cf. Houben-Weyl, Methoden der OrganischenChemie [Methods of Organic Chemistry], Vol. E5/1 and E5/2, Georg ThiemeVerlag, Stuttgart 1985).

Compounds of the formula I where R⁹═S(O)_(n)R¹⁰ (n=1, 2), P(O)(R¹⁰)_(n)(n=1, 2) or C(S)R¹⁰ can of course also be prepared by fragment coupling,such as described above, which is advisable, for example, when, forexample, a (commercially available) aminosulfonic acid, aminosulfinicacid, aminophosphonic acid or aminophosphinic acid or derivativesderived therefrom, such as esters or amides, are contained in F-G of theformula I.

Compounds of the formula I in which R¹—Y-A- is

or cyclic acylguanidines of the type

can be prepared, for example, by reacting a compound of the formula IIIQ(O)C—B-O-E-F-G   III

in which Q is an easily nucleophilically substitutable leaving group,with the appropriate guanidine (derivative) of the type

or the cyclic guanidine (derivative) of the type

The activated acid derivatives of the formula III, in which Q is analkoxy group, preferably a methoxy group, a phenoxy group, a phenylthioor methylthio 2-pyridylthio group, a nitrogen heterocycle, preferably1-imidazolyl, are advantageously obtained in a manner known per se fromthe carboxylic acids (Q=OH) or carbonyl chlorides (Q=Cl) on which theyare based. The latter are in turn obtained in a manner known per se fromthe carboxylic acids (Q=OH) on which they are based, for example byreaction with thionyl chloride.

Beside the carbonyl chlorides (Q=Cl), further activated acid derivativesof the type Q(O)C— can be prepared in a manner known per se directlyfrom the carboxylic acids (Q=OH) on which they are based, such as, forexample, the methyl esters (Q=OCH₃) by treating with gaseous HCl inmethanol, the imidazolides (Q=1-imidazolyl) by treating withcarbonyidiimidazole (cf. Staab. Angew. Chem. Int. Ed. Engl. 1, 351-367(1962)], the mixed anhydrides (Q=C₂H₅OC(O)O or TosO) with Cl—COOC₂H₅ ortosyl chloride in the presence of triethylamine in an inert solvent. Theactivation of the carboxylic acids can also be carried out withdicyclohexylcarbodiimide (DCCI) or withO-[(cyano(ethoxy-carbonyl)methylene)amino]-1,1,3,3-tetramethyluroniumtetrafluoroborate (“TOTU”) [Weiss and Krommer, Chemiker Zeitung 98, 817(1974)] and other activating reagents customary in peptide chemistry. Anumber of suitable methods for the preparation of activated carboxylicacid derivatives of the formula II are indicated stating sourceliterature in J. March. Advanced Organic Chemistry, Third Edition (JohnWiley & Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative of the formulaIII with the respective guanidine (derivative) is carried out in amanner known per se in a protic or aprotic polar but inert organicsolvent. In this context, methanol, isopropanol or THF from 20° C. up tothe boiling temperature of these solvents have proven suitable in thereaction of the methyl esters (Q=OCH₃) with the respective guanidines.In the case of most reactions of compounds of the formula III withsalt-free guanidines, the reaction is advantageously carded out inaprotic inert solvents such as THF, dimethoxyethane, dioxane. However,if a base (such as, for example, NaOH) is used, it is also possible touse water as a solvent in the reaction of compounds of the formula IIIwith guanidines. If Q=Cl, the reaction is advantageously carried outwith addition of an acid scavenger, e.g. in the form of excess guanidine(derivative) to bind the hydrohalic acid.

Compounds of the formula I in which R¹—Y-A- is R²—C(═NR²)—C(O)— or asystem comprising a mono- or polycycle of the type

can be obtained analogously.

Compounds of the formula I in which R¹—Y-A is a sulfonyl- orsulfoxylguanidine of the type R²R³N—C(═NR²)—NR²—S(O)_(n)— (n=1, 2) or asulfonyl- or sulfoxylaminoguanidine of the typeR²R³N—C(═NR²)—NR²—NR²—S(C)_(n)— (n=1, 2) or

are prepared by processes known from the literature by reaction ofR²R³N—C(═NR²)—NR²H or R²R³N—C(═NR²)—NR²—NR²H or

with sulfinic or sulfonic acid derivatives of the formula IVQ-S(O)_(n)—B—O-E-F-G   IVin which Q, for example, is Cl or NH₂, analogously to S. Birtwell etal., J. Chem. Soc. (1946) 491 or Houben-Weyl, Methoden der OrganischenChemie [Methods of Organic Chemistry], Vol. E4, Georg Thieme Verlag,Stuttgart 1983; p. 620 et seq.

Compounds of the formula I in which R¹—Y-A- is R²—C(═NR)—NR²—S(O)_(n)—(n=1, 2) or R²—C(═NR²)—NR²—NR²—S(O)_(n)— (n=1, 2) or a system comprisinga mono- or polycycle of the type

(n=1, 2) can be obtained analogously.

Compounds of the formula I in which Y has the meaning indicated, A is—NR²—C(O)—NR²—, —NR²—C(O)O—, —NR²—C(O)S— and R¹ is R²R³N—C(═NR²)—,R²—C(═NR²)— or a 4-10-membered mono- or polycyclic, aromatic ornonaromatc ring system which is specified as described above and can besubstituted as described there, are prepared, for example, by reacting acompound of the formula VQ-B-D-E-F-G   Vin which Q is HNR²—, HO— or HS—, with a suitable carbonic acidderivative, preferably 1 5 phosgene, diphosgene (trichloromethylchloroformate), triphosgene (bistrichloromethyl carbonate), ethylchloroformate, i-butyl chloroformate, bis(1-hydroxy-1-H-benzotriazolyl)carbonate or N,N′-carbonyidiimidazole, in a solvent which is inert tothe reagents used, preferably DMF, THF or toluene, at a temperaturebetween −20° C. and the boiling point of the solvent, preferably between0° C. and 60° C., first to give a substituted carbonic acid derivativeof the formula VI

in which R is —NR²—, —O— or —S— and Q′, depending on the carbonic acidderivative used, is chlorine, ethoxy, isobutoxy, benzotriazol-1-oxy or1-imidazolyl.

The reaction of these derivatives—in the case where Y is a directbond—with R²R³N—C(═NR²)—NR²H or R²—C(═NR)—NR²H or, if Y is —NR²—, withR²R³N—C(═NR²)—NR²—NR²H or R²—C(═NR²)—NR²—NR²H or with the systemscomprising a mono- or polycycle of the type

is carried out as described above in the preparation of acylguanidine(derivatives).

Compounds of the formula I in which F is —R²N—C(O)—NR²— or—R²N—C(S)—NR²— are prepared, for example, by reacting a compound of theformula VIIR¹—Y-A-B-D-E-NHR²   VIIwith an isocyanate OCN-G or isothiocyanate SCN-G by processes known fromthe literature.

Compounds of the formula I, in which F is —C(O)NR²—, —SO₂NR²— or —C(O)O—can be prepared, for example, by reaction ofR¹—Y-A-B-D-E-C(O)Q or R¹—Y-A-B-D-E-SO₂Q(Q is an easily nucleophilically substitutable leaving group, such as,for example, OH, Cl, OCH₃ etc.) with HR²N-G or HO-G by processes knownfrom the literature.

Compounds of the formula I in which Y is a bond and R¹-A- comprises amono- or polycycle of the type

can be prepared, for example, by reacting a compound of the formula VIIIHR²N—B-D-E-F-G   VIIIwith a mono- or polycycle of the type

in which X is a nucleophilically substitutable leaving group such as,for example, halogen or SH, SCH₃, SOCH₃, SO₂CH₃ or HN—NO₂, by processesknown from the literature (see, for example, A. F. Mckay et al., J. Med.Chem. 6 (1963) 587, M. N. Buchman et al., J. Am. Chem. Soc. 71 (1949),766, F. Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba et al.,Eur. J. Med. Chem. 21 (1986), 391).

Compounds of the formula I in which Y is a bond and R¹-A- comprises amono- or polycycle of the type

can be prepared, for example, by reacting a compound of the formula VIIIwith a compound of the type

in which X is a leaving group, such as, for example —SCH₃, by processesknown from the literature (cf., for example, T. Hiroki et al., Synthesis(1984) 703 or M. Purkayastha et al., Indian J. Chem. Sect B 30 (1991)646).

Compounds of the formula I in which D is —C≡C— can be prepared, forexample, by reacting a compound of the formula IXX-E-F-G   IXin which X is I or Br with a compound of the type R¹—Y-A-B—C≡CH in apalladium-catalyzed reaction, such as described, for example, in A.Arcadi et al., Tetrahedron Lett. 1993, 34, 2813 or E. C. Tayloret al. J.Org. Chem. 1990, 55, 3222.

Analogously, compounds of the formula I in which F is —C≡C— can beprepared, for example, by linkage of compounds of the formula XR¹—Y-A-B-D-E-X   Xin which X is I or Br with a compound of the type HC≡C-G in apalladium-catalyzed reaction.

Preparation processes known from the literature are described, forexample, in J. March, Advanced Organic Chemistry, Third Edition (JohnWiley & Sons, 1985).

The compounds of the formula I according to the invention inhibit boneresorption by osteoclasts. Bone diseases against which the compoundsaccording to the invention can be employed are especially osteoporosis,hypercalcemia, osteopenia, e.g. caused by metastases, dental disorders,hyperparathyroidism, periarticular erosions in rheumatoid arthritis andPaget's disease.

The compounds of the formula I can furthermore be employed for thealleviation, avoidance or therapy of bone disorders which are caused bya glucocorticoid, steroid or corticosteroid therapy or by a deficiencyof sex hormone(s). All these disorders are characterized by bone loss,which is based on the inequilibrium between bone formation and bonedestruction.

The compounds of the formula I can furthermore be used as carriers foractive compounds in order to transfer the active compounds specificallyto the site of action (=drug targeting, see, for example, Targeted DrugDelivery, R. C. Juliano, Handbook of Experimental Pharmacology Vol. 100,Ed. Born, G. V. R. et al., Springer Verlag). The active compounds arethose which can be used for the treatment of the abovementioneddiseases.

The compounds of the formula I and their physiologically tolerable saltscan be administered to animals, preferably to mammals, and in particularto humans as medicaments by themselves, in mixtures with one another orin the form of pharmaceutical preparations which allow enteral orparenteral administration and which as an active constituent contain anefficaceous dose of at least one compound of the formula I or of a saltthereof, in addition to customary pharmaceutically innocuous excipientsand additives. The preparations normally contain approximately 0.5 to90% by weight of the therapeutically active compound.

The medicaments can be administered orally, e.g. in the form of pills,tablets, lacquered tablets, sugar-coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration can also be carried out rectally,however, e.g. in the form of suppositories, or parenterally, e.g. in theform of injection or infusion solutions, microcapsules or rods,percutaneously, e.g. in the form of ointments or tinctures, or nasally,e.g. in the form of nasal sprays.

The pharmaceutical preparations are prepared in a manner known per se,pharmaceutically inert inorganic or organic excipients being used. Forthe production of pills, tablets, sugar-coated tablets and hard gelatincapsules, it is possible to use, for example, lactose, maize starch orderivatives thereof, talc, stearic acid or its salts etc. Excipients forsoft gelatin capsules and suppositories are, for example, fats, waxes,semisolid and liquid polyols, natural or hardened oils, etc. Suitableexcipients for the preparation of solutions and syrups are, for example,water, sucrose, invert sugar, glucose, polyols, etc. Suitable excipientsfor the production of injection solutions are water, alcohols, glycerol,polyols, vegetable oils, etc. Suitable excipients for microcapsules,implants or rods are copolymers of glycolic acid and lactic acid.

Beside the active compounds and excipients, the pharmaceuticalpreparations can also contain additives, such as, for example, fillers,extenders, disintegrants, binders, lubricants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings or aromatizers, thickening agents, diluents, buffersubstances, furthermore solvents or solubilizers or agents for achievinga depot effect, and salts for altering the osmotic pressure, coatingagents or antioxidants. They can also contain two or more compounds ofthe formula I or their physiologically tolerable salts; furthermorebeside at least one compound of the formula I, also one or more othertherapeutically active substances.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. In the case of oraladministration, the daily dose is in general from 0.01 to 50 mg/kg,preferably 0.1 to 5 mg/kg, in particular 0.3 to 0.5 mg/kg, of bodyweightto achieve efficacious results: in the case of intravenousadministration the daily dose is in general approximately 0.01 to 100mg/kg, preferably 0.05 to 10 mg/kg, of body weight. In particular in thecase of the administration of relatively large amounts, the daily dosecan be divided into more than one, e.g. 2, 3 or 4, part administrations.In some cases it may be necessary, depending on individual behavior, todeviate upward or downward from the daily dose indicated.

The present invention will now be further described by reference to thefollowing non-limiting examples.

EXAMPLES

The products were identified by means of mass spectra and/or NMRspectra.

Example 1(2S)-2-(1-Adamantyl-methyloxycarbonylamino)-3-4-(3-guanidinocarbonyl-propyloxy)phenyl)propionicacid (1.5)

The synthesis was carried out according to the following reactionsequence:

1a) tert-Butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonyl-propyloxy)phenyl)propionate(1.1)

8.29 ml (57.9 mmol) of ethyl 4-bromobutanoate and 28.21 g (86.58 mmol)of cesium carbonate were added to 21.5 g (57.9 mmol) of tert-butylN-benzyloxycarbonyltyrosine in 280 ml of acetone and the mixture washeated to reflux with stirring. After 2 h, a further 2 ml of ethyl4-bromobutancate and 2 g of cesium carbonate were added, after a further2 h a further 2 ml of ethyl 4-bromobutancate and 3 g of cesium carbonatewere added and after standing at room temperature overnight 9 ml ofethyl 4-bromobutanoate were added again and the mixture was heated toreflux for a further 6 h. After cooling, it was filtered, the residuewas washed with acetone and the filtrate was concentrated. The residuewas taken up in diethyl ether and the organic phase was washedsuccessively with 3% strength citric acid solution, 3×H₂O and saturatedNaCl solution. The ether phase was dried over MgSO₄, the drying agentwas filtered off and the filtrate was concentrated in vacuc. The residuewas chromatographed on silica gel using CH₂Cl₂ and CH₂Cl₂/MeOH (99/1).31.3 g of a pale yellow oil were obtained, which was employed withoutfurther purification for the synthesis of (1.2).

1b) tert-Butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-guanidinocarbonyl-propyloxy)phenyl)propionate(1.2)

A solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tert-butanolwas added to a solution of 20 g (41.23 mmol) of (1.1) in THF and themixture was stirred at room temperature for 18 h. A further 4.5 g ofguanidine in 150 ml of tert-butanol were then added, and the reactionsolution was stirred at room temperature for 7 h, concentrated to abouta half and stirred at room temperature for a further 18 h. The solventwas removed in vacuo and the residue was first filtered through basicAl₂O₃ using CH₂Cl₂/MeOH/H₂O (95/5/0.5) and then chromatographed onsilica gel by means of MPLC using CH₂Cl₂/MeOH/acetic acid (90/10/0.5).8.6 g (42%) of (1.2) were obtained.

1c) (2S)-2-Amino-3-(4-(3guanidinocarbonylpropyloxy)phenyl)propianic acidhydrochloride (1.3)

30 ml of 95% strength trifluoroacetc acid were added to 8.6 g (17.3mmol) of (1.2) and the mixture was stirred at room temperature for 25min. The reaction mixture was concentrated in a rotary evaporator andthen concentrated twice with toluene. The residue was taken up in diluteacetic acid, treated with water and freeze-dried. The colorless solidthus obtained was purified on silica gel by means of MPLC usingCH₂Cl₂/MeCH/acetic acid (90/10/0.5). After concentrating andfreeze-drying, 5.5 g (72%) of a colorless solid were obtained.

400 mg of this substance were dissolved in 30 ml of MeOH and afteraddition of methanolic hydrogen chloride solution the benzyloxycarbonylprotective group was cleaved hydrogenolytically over 10% Pd/C. Theprecipitated product was dissolved by addition of DMF, the catalyst wasfiltered off, the filtrate was concentrated and the residue wasfreeze-dried. 320 mg of (1.3) were obtained as a colorless solid.

1d) 1-Adamantylmethyl 4-nitrophenylcarbonate (1.4)

605 mg (3 mmol) of 4-nitrophenyl chloroformate were added to a solutionof 499 mg (3 mmol) of 1-hydroxymethyladamantane in 7 ml of pyridine andthe mixture was stirred overnight at room temperature. Afterconcentrating in a high vacuum, the residue was employed directly forthe preparation of (1.5).

1e)(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(3-guanidinocarbonylpropyloxy)phenyl)propionicacid (1.5)

114.5 mg of (1.4) were added to a solution of 146 mg (0.35 mmol) of(1.3) in 2 ml of DMF and the mixture was stirred overnight at roomtemperature. 0.059 ml of diisopropylethylamine was added and the mixturewas again stirred overnight at mom temperature. After removing thesolvent in vacuo, the residue was partitioned between ethyl acetate andwater. The organic phase was dried over MgSO₄, concentrated and thentreated with diisopropyl ether. The precipitate was filtered off andpurified by means of preparative thin-layer chromatography usingCH₂Cl₂/MeOH/acetic acid (100/25/2). 10 mg of (1.5) were obtained.

Example 2(2S)-2-(2(1-Adamantyl)ethyl)oxycarbonylamino)-3-(4-(3guanidinocarbonyl-propyloxy)phenyl)propionicacid (2.2)

The synthesis was carried out according to the following reactionsequence:

The synthesis of (1.3) was carried out as described in Example 1c).Compound (2.1) was prepared from 1-(2-hydroxyethyl)adamantane and4-nitrophenyl chloroformate analogously to the synthesis of compound(1.4) (Example 1d) and employed directly for the synthesis of (2.2).

(2S)-2-((2-(1-Adamantyl)ethyl)oxycarbonylamino)-3-(4-(3-guanidinocarbonyl-propyloxy)phenyl)propionicacid (2.2)

119 mg of (2.1) were added to a solution of 146 mg (0.35 mmol) of (1.3)in 2 ml of DMF and the mixture was stirred overnight at roomtemperature. 2.3 mg of imidazole and 0.3 ml of pyridine were added andthe mixture was again stirred overnight at room temperature. Thesolution was concentrated, the residue was partitioned between water andethyl acetate, the organic phase was dried over MgSO, and, afterfiltration, the solvent was removed in vacuo. The residue was separatedby means of preparative thin-layer chromatography usingCH₂Cl₂/MeOH/acetic acid (100/25/2). 19 mg of (2.2) were obtained.

Example 3(2S)-2-1-Adamantyimethyloxycarbonylamino)-3-(4-(2(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid (g)

The synthesis was carried out according to the following reactionsequence

3a) 4-(2-Methoxycarbonylvinyl)benzoic acid

18.74 g (0.12 mol) of potassium monomethyl malonate were suspended in 18ml of pyridine. 15.01 g (0.1 mol) of 4 carboxybenzaldehyde and 0.85 g(0.01 mol) of piperidine were added at room temperature (RT) withstirring and the mixture was boiled under reflux until the evolution ofCO₂ had ended (about 2 h). A further 60 ml of pyridine were added andthe mixture was stirred under reflux for a further 1 h. The reactionmixture was treated with stirring with 500 ml of ice and 110 ml of conc.HCl. After addition was complete, the mixture was stirred for a further20 min. and the product was filtered off with suction, washed with waterand recrystallized from isopropanol. Yield: 12.85 g (62%).

¹H NMR (200 MHz, DMSO): δ=3.75 (s, 3H, OCH₃); 6.76 (d, J=15 Hz. 1H,CHCOCH₃); 7.73 (d, J=15 Hz, 1H, Ar—CH); 7.84 (d, J=9 Hz 2H, Ar—H); 7.98(d, J=9 Hz, 2H, Ar—H); 13.11 (s, broad, 1H, COOH)

MS: Cl⁺, m/e=207.2 (M+H⁺, 100%)

HPLC: (RP18: Nucleosil 300-5-C18, 250×4 mm), buffer A: H₂O, 0.1% TFA;buffer B: acetonitrile (80% v/v); H₂O (20% v/v); 0.1% TFA; gradient: (1)5 min, 10% buffer B; (2) over 20 min to 90% buffer B: (3) 5 min 90%buffer B; flow rate 1milmin; R_(t)=18.05 min.

3b) 4-(2-Methoxycarbonylethyl)benzoic acid

8 g (38.8 mmol) of 4-(2-methoxycarbonylvinyl)benzoic acid (Example 3a)were suspended in 250 ml of dioxane and hydrogenated with 1 bar H₂ overPd/C (10%) at RT for 7 h. The mixture was filtered and the solvent wasevaporated in vacuo. Yield: 8.05 g (100%).

¹H-NMR (200 MHz, OMSO): d=2.67 (t, J=8 Hz, 2H, CH ₂—COOMe); 2.93 (t, J=8Hz, 2H, Ar—CH₂); 3.59 (s, 3H, OCH₃); 7.35 (d, 2H, Ar—H); 7.86 (d, J=9Hz, 2H, Ar—H); 12.80 (s, broad, 1H, COOH)

MS: Cl⁺, m/e=209.2 (M+H⁺, 100%)

HPLC: (RP18: Nucleosil 300-5-C18, 250×4 mm), buffer A: H₂O, 0.1% TFA;buffer B: acetonitrile (80% v/v); H₂O (20% v/v); 0.1% TFA; gradient: (1)5 min, 10% buffer B; (2) over 20 min to 90% buffer B; (3) 5 min 90%buffer B; flow rate 1ml/min; R_(t)=17.03 min.

3c) tert-Butyl(2S)-2-benzytoxycarbonyiamino-3-(4-(2-methoxycarbonyl-ethyl)benzoylamino)propionate

354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid (Example 3b)and 500 mg (1.7 mmol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3-amino-propionate were dissolved in 3 mlof DMF and treated with 557 mg (1.7 mmol) ofO-[(cyano(ethoxycarbonyl)methylidene)amino]-1,1,3,3,-tetramethyluroniumtetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine(DIPEA) and the solution was stirred at RT for 7 h. The solvent wasevaporated in vacuo, the residue was dissolved in ethyl acetate (EA) andwashed three times each with KHSO₄ and NaHCO₃ solution until neutral,the organic phase was separated off and dried, and the solvent wasdistilled off in vacuo. Yield: 770 mg (93%).

MS: ES⁺, m/e=485.2 (M+H⁺, 100%)

3d) tert-Butyl(2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionate

1.25 g (9.2 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochlorideand 1.03 g (9.2 mmol) of potassium tert-butoxide were dissolved in 3 mlof absol. DMF and the mixture was stirred at RT for 30 min. 740 mg (1.53mmol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-2-methoxycarbonylethyl)benzoylamino)propionate(Example 3c) in 1 ml of DMF were then added and the mixture was stirredat RT for 4 h. It was adjusted to pH 4 using glacial acetic acid, thesolvent was stripped off in vacuo, and the residue was chromatographedon silica gel (dichloromethane/methanol/glacial acetic acid/water(9/1/0. 1/0.1)).

Yield: 190 mg (38%).

MS: ES⁺, m/e=552.3 (M+H⁺, 100%)

3e)(2S)-2-Benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid

190 mg (0.34 mmol) of tert-butyl2S-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionate(Example 3d) were dissolved in 5 ml of 95% trifluoroacetic acid and themixture was stirred at RT for 1 h. The trifluoroacetic acid wasdistilled off in vacuo, the mixture was coevaporated with toluene, theresidue was dissolved in glacial acetic acid, and the solution wasdiluted with water and freeze-dried.

Yield: 170 mg (100%).

MS: ES⁺, m/e=496.3 (M+H⁺, 100%)

3f)(2S)-2-Amino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)benzoylamino)propionicacid

100 mg (0.2 mmol) of(2S)-2-benzyloxycarbonylamino-3-(4(2-(1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid (Example 3e) were dissolved in 15 ml of dioxane, treated with 0.012ml of glacial acetic acid and hydrogenated at RT and 1 bar H₂ over Pd/C(5%). After 2 h, 15 ml of methanol were added and the mixture washydrogenated at RT and 1 bar H₂ for a further 5 h. It was filtered andthe solvent was evaporated in vacuo. Yield: 67.4 mg (93%).

MS: ES⁺, m/e=362.2 (M+H⁺, 30%); 173.0 (100).

3g)(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(2-(1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid

67.4 mg (0.186 mmol) of2S-amino-3-4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid (Example 3f) were dissolved in 4 ml of dioxane. With stirring,first 4 ml of saturated NaHCO₃ solution, then 57 mg of 1-adamantylmethyl2,5-dioxopyrrolidin-1-yl carbonate were added at RT. The mixture wasstirred at RT for 24 h and adjusted to pH 4 using glacial acetic acid,the solvent was stripped off in vacuo and the residue waschromatographed (20% (vtv) acetonitrile in water, 0.1% trifluoroaceticacid, up to 40% (v/v) acetonitrile) on RP-18 (Uchrospher C-18). Yield:30 mg (30%).

MS: ES⁺, m/e=554.4 (M+H⁺, 100%).

Example 4(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylarbamoyl)propyloxy)phenyl)propionicacid

4a) tert-Butyl(2S)-2-amino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate (4.2)

100 g (0.206 mol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxy-carbonylpropyloxy)phenyl)propionate(1.1) from Example 1 were dissolved in 1 liter of methanol, the solutionwas treated with methanolic hydrogen chloride solution and with 10 g of20% palladium hydroxide/carbcn and hydrogen was passed in for 6 hours.Then the catalyst was filtered off, the solution was evaporated and theresidue was treated with tert-butylether. The precipitate formed wasfiltered off. 72 g (90%) of an amorphous powder were obtained.

4b) tert-Butyl(2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-(3-ethoxy-carbonylpropyloxy)phenyl)propionate(4.3)

892 mg (5.5 mmol) of carbonyidiimidazole (CDI) were added to a solutionof 830 mg (5 mmol) of 1-hydroxymethyladamantane in 10 ml oftetrahydrofuran and the mixture was stirred overnight at RT. It was thentreated with 1 g (2.57 mmol) of tert-butyl(2S)-2-amino-3-(4-(3ethoxycarbonyl-propyloxy)phenyl)propionate and 442μl (2.57 mmol) of diisopropylethylamine (DIPEA) and the mixture wasstirred overnight at 50° C. After cooling, it was taken up in ethylacetate and the organic phase was washed successively with 3% strengthcitric acid solution, sodium hydrogencarbonate solution, 3×H₂O andsaturated NaCl solution. The organic phase was dried using MgSO₄, thedrying agent was filtered off and the filtrate was concentrated. Theresidue was chromatographed on silica gel using CH₂Cl₂/CH₃OH (99/1).1.19 g (85%) of an oil were obtained. which was employed without furtherpurification for the synthesis of (4.4). 4c) tert-Butyl(2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-(3-(1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)propoxy)phenyl)propionate(4.4)

398 mg (2.94 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloridewere dissolved in 7 ml of methanol and treated with 330 mg (2.94 mmol)of potassium tert-butoxide. After 40 min, the precipitated salts werefiltered off and the filtrate was concentrated. The residue wasdissolved in 3 ml of dimethylformamide and added to a solution of 365 mgof tert-butyl(2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-(3-ethoxycarbonylpropyloxy)-phenyl)propionate(4.3). The mixture was warmed at 40° C. for 5 hours, the solvent wasremoved in vacuo, the residue was taken up in ethyl acetate and theorganic phase was washed 3× with H₂O and saturated sodium chloridesolution. The organic phase was concentrated and the residue waschromatographed on silica gel using CH₂Cl₂/CH₃OH/ethyl acetate/H₂O(90:10:0.5:0.5). 100 mg of an amorphous powder were obtained, which wasemployed without further purification for the synthesis of (4.5).

4d)(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(3-1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)propyloxy)phenylpropionicacid (4.5)

100 mg of the tert-butyl ester of Example 4.4 were dissolved in 10 ml oftrifluoroacetic acid/H₂O (95:5). After 30 min, the reaction solution wasconcentrated and the residue was digested with diisopropyl ether. Bysubsequent freeze-drying, 85 mg of (4.5) were obtained.

Example 5(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(3-(4,5-dihydroimidazol-2-ylcarbamoyl)propyloxy)phenyl)propionicacid (5.2)

The synthesis was carried out analogously to Example 4.

5a) tert-Butyl(2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-3-(4,5-dihydroimidazol-2-ylcarbamoyl)propyloxy)phenyl)propionate(5.1)

436 mg (0.8 mmol) of tert-butyl(2S)-2(1-adamantylmethyloxycarbonylamino)-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionatewere added to a solution of 388 mg (3.2 mmol) of2-amino-4,5-dihydroimidazole hydrochloride and 359 mg (3.2 mmol) ofpotassium tert-butoxide in 10 ml of DMF. The mixture was stirredovernight. After the reaction had ended, it was worked up analogously toExample 4c and chromatographed on silica gel using the same eluentmixture. 188 mg (0.32 mmol) of (5.1) were obtained.

5b)(2S)-2-(1-Adamantylmethyloxycarbonylamino)-3-(4-(3-(4,5-dihydroimidazol-2-ylcarbamoyl)propyloxy)phenyl)propionicacid (5.2)

188 mg (0.32 mmol) of (5.1) were dissolved in 10 ml of trifluoroaceticacid/H₂O (95:5). After 30 min, the solvent was removed in vacuc and theresidue was digested with diisopropyl ether. After freeze-drying, 168 mgof an amorphous powder of (5.2) were obtained.

Pharmacological Testing

The inhibition of bone resorption by the compounds according to theinvention can be determined, for example, with the aid of an osteoclastresorption test (“PIT ASSAY”), for example analogously to WO 95/32710.

The inhibitory action of the compounds according to the inventionagainst the vitronectin receptor α_(v)β₂ can be determined, for example,as described below:

Test for the measurement of the inhibition of the binding of 293 cellsto human vitronectin (abbreviated in the test results to Vn/293 celltest)

1. Purification of Human Vitronectin

Human vitronectin was isolated from human plasma and purified byaffinity chromatography according to the method of Yatohyo et al., CellStructure and Function, 1988, 23, 281-292.

2. Cell Test

293 cells, a human embryonic kidney cell line, which were cotransfectedwith DNA sequences for the α_(v) and β₃ subunits of the vitronectinreceptor were selected according to the FACS method with a view to ahigh expression rate (>500,000 α_(v)β₃ receptors/cell). The selectedcells were cultured and sorted again by means of FACS to obtain a stablecell line (15 D) with expression rates of >1,000,000 copies of α_(v)β₃per cell.

A Linbro 96-well tissue culture plate with a flat bottom was coatedovernight at 4° C. with human vitronectin (0.01 mg/ml, 0.05 ml/well) inphosphate-buffered saline solution (PBS) and then blocked with 0.5%strength BSA. Solutions of the test substances from 10⁻¹⁰−2×10⁻³ mol/lin glucose-containing DMEM medium were prepared and in each case 0.05ml/well of the solution was added to the plates. The cells whichexhibited high levels of α_(v)β₃ (e.g. 15 D) were suspended inglucose-containing OMEM medium and the suspension was adjusted to acontent of 25,000 cells/0.05 ml of medium, 0.05 ml of this cellsuspension was added to each well and the plate was incubated at 37° C.for 90 min. The plate was washed 3× with warm PBS to remove unboundcells. The bound cells were lyzed in citrate buffer (25 mmol, pH 5.0),which contained 0.25% Triton X-100. The hexose amidase substratep-nitrophenyl-N-acetyl-β-D-glucosaminide was then added and the platewas incubated at 37° C. for 90 min. The reaction was stopped with aglycine (50 mmol)/EDTA (5 mmol) buffer (pH 10.4) and the absorption ofeach well was measured at 405-650 nm. The data were evaluated usingstandard methods.

The following test results were obtained. Vn/293 Cell test IC₅₀ (μM)Compound of example 1 0.032 Compound of example 3 0.032

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification beconsidered as exemplary only, with the true scope and spirit of theinvention being indicated by the following claims.

All references referred to herein are expressely incorporated byreference in their entireties.

Priority application Federal Republic of Germany No. 19629816.4 filed onJul. 24, 1996 including the title, specification, claims and abstract,is hereby incorporated by reference.

1.-19. (canceled)
 20. A process for the preparation of a compound offormula (I)R¹—Y-A-B-D-E-F-G   (I), in which R¹—Y-A- is:

or a cyclic acylguanidine of the type

wherein B is a direct bond, (C₁-C₁₀)-alkanediyl, —CR²═CR³— or —C≡C—,which in each case can be mono- or disubstituted by (C₁-C₈)-alkanediyl;D is a direct bond, (C₁-C₈)-alkanediyl, —O—, —NR²—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—, —CO—, —CS—, —S(O)—,—S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)—, —NR²—S(O)₂—, —S—, —CR²═CR³—, —C≡C—, or—CH(OH)—, which in each case can be mono- or disubstituted by(C₁-C₈)-alkanediyl; E is a 6-membered aromatic ring system, whichoptionally contains up to 4 nitrogen atoms and is optionally substitutedby 1-4 identical or different radicals selected from the groupconsisting of R², R³, fluorine, Cl, Br, I, NO₂ and OH; F is a directbond, (C₁,-C₈)-alkanediyl, —O—, —NR²—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—, —CO—, —CS—, —S(O)—,—S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)—, —NR²—S(O)₂—, —S—, —CR²═CR³—, —C≡C—, or—CH(OH)—, which in each case can be mono- or disubstituted by(C₁-C₈)-alkanediyl;

R² and R³, independent of one another, are H, (C₁-C₁₀)-alkyl which isoptionally mono-or polysubstituted by fluorine, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-arylene-R⁷,(C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, H₂N, (R⁸O)R⁸NR⁷, R⁸OR⁷R⁸OC(O)R⁷,R⁸—(C₅-C₁₄)-arylene-R⁷, R⁸R⁸NR⁷, HO—(C₁-C₈)-alkanediyl-NR⁸R⁷,R⁸R⁸NC(O)R⁷, R⁸C(O)NR⁸R⁷, R⁸C(O)R⁷, R⁸R⁸N—C(═NR⁸)—, R⁸R⁸N—C(═NR⁸)—NR⁸—or (C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkanediyloxycarbonyl; R⁴ is(C₁₀-C₁₈)-cycloalkyl, (C₁₀-C₁₈)cycloalkyl-(C₁-C₈)-alkanediyl, whereinthe cycloalkyl radicals are mono- or polycyclic, saturated or mono- orpolyunsaturated and may be optionally substituted with (C₁-C₁₀)-alkylwhich may be optionally substituted with at least one substituentselected from the group consisting of fluorine, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₃)-alkanediyl, (C₅-C₁₄)-aryl,(C₅-C₁₄)-aryl-(C₁-C₃)-alkanediyl, (C₁-C₈)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyloxy, (C₅-C₁₄)-aryloxy,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₁₄)-alkanediyloxy, NH₂, mono- ordi-(C₁-C₈-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylamino,(C₅-C₁₄)-arylamino, ═O, ═S, NO₂, OH, fluorine, Cl, Br, or I; R⁶OR⁷,R⁶SR⁷, R⁶CO₂R⁷, R⁶OC(O)R⁷, R⁶—(C₅-C₁₄)-arylene-R⁷, R⁵N(R²)R⁷, R⁶R⁸NR⁷,R⁶N(R²)C(O)OR⁹, R⁶S(O)_(n)N(R²)R⁷, R⁶OC(O)N(R²)R⁷, R⁶C(O)N(R²)R⁷,R⁶N(R²)C(O)N(R²)R⁷, R⁶N(R²)S(O)_(n)N(R²)R⁷, R⁶S(O)_(n)R⁷;R⁶SC(O)N(R²)R⁷, R⁶C(O)R⁷, R⁶N(R²)C(O)R⁷, or R⁶N(R²)S(O)_(n)R⁷; R⁵ is H,fluorine, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl, (C₅-C₁₄)-aryl, or(C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyl, wherein the alkyl radicals may bemono- or polysubstituted by fluorine; R⁶ is (C₁₀-C₁₈)-cycloalkyl or(C₁₀-C₁₈)-cycloalkyl-(C₁-C₈)-alkanediyl, wherein the cycloalkyl radicalsare mono- or polycyclic, saturated or mono- or polyunsaturated, and maybe mono- or polysubstituted by (C₁-C₁₀)-alkyl which is optionally mono-or poly-substituted by fluorine, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₃)-alkanediyl, (C₅-C₁₄)-aryl,(C₅-C₁₄)-aryl-(C₁-C₃)-alkanediyl, (C₁-C₈)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyloxy, (C₅-C₁₄)-aryloxy,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy, NH₂, mono- ordi-(C₁-C₈-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylamino,(C₅-C₁₄)-arylamino, ═O, ═S, NO₂, OH, fluorine, Cl, Br, or I; R⁷ is adirect bond or (C₁-C₅)-alkanediyl; R⁸ is H, (C₁-C₈)-alkyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkanediyl,(C₅-C₁₄)-aryl, or (C₅-C₄)-aryl-(C₁-C₈)-alkanediyl, wherein the alkylradicals may be mono- or polysubstituted by fluorine; R⁹ is C(O)R¹⁰,C(S)R¹⁰, S(O)_(n)R¹⁰, P(O)(R¹⁰)₂ or a four- to eight-membered, saturatedor unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S; R⁹ is OH,(C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediyloxy, (C₅-C₁₄)-aryloxy,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkanediyloxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylcarbonyloxy-(C₁-C₈)-alkanediyloxy, NH₂,mono- or di-(C₁-C₅-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkanediylamino,(C₁-C₈)dialkylaminocarbonylmethylenoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethylenoxy,(C₅-C₁₄)-arylamino or a radical of an L- or D-amino acid; n is 1 or 2; qis 0 or 1; which comprises reacting a compound of the formula (III)Q(O)C—B-D-E-F-G   (III) in which Q is an easily nucleophilicallysubstitutable leaving group and B, D, E, F and G are as defined above,with the appropriate guanidine (derivative) of the type

or the cyclic guanidine (derivative)

in which R² and R³ are as defined above.